Introduction: Phenylacetaldehyde (PAA), a product of phenylalanine metabolism, is generated by microbiota and has demonstrated anticancer properties in breast cancer. As the gut microbiome influences intestinal homeostasis, we investigated the effects of PAA on colorectal cancer (CRC). Methods: Serum PAA levels and feces microbiota from 30 CRC patients and 30 healthy controls were analyzed by targeted GC-MS/MS and metagenomic sequencing. A validation cohort of 75 CRC patients and 53 healthy controls was analyzed for PAA level in serum. CRC cell lines and CRC-patient derived organoids were cultured and treated with PAA alone and in combination with 5-fluouracil (5-FU, standard chemotherapy used for CRC), then evaluated for viability, proliferation, cell cycle distribution, and cell death in vitro. We interrogated the mechanistic pathways induced by PAA treatment using RNA sequencing and western blot. Results: PAA levels were significantly decreased in the circulation of CRC patients compared to healthy controls in our study population and the validation cohort. Metagenomic sequencing indicated the bacteria that positively correlated with PAA levels were significantly more abundant in healthy controls; while bacteria that negatively correlated with PAA were more abundant in CRC. In vitro, PAA inhibited the viability and colony formation of CRC cell lines as well as human-derived organoids in a concentration-dependent manner. Mechanistically, PAA treatment induced a P53-dependant G1 cell cycle arrest and cell death in HCT116 and RKO cell lines. Proteomic analysis also demonstrated a downregulation in PI3K/AKT/mTOR and ERK pathways. Investigation by RNA sequencing showed that PAA inhibits CRC by inducing endoplasmic reticulum stress-induced autophagy. When combined with 5-FU, PAA enhanced the potency of 5-FU on viability, cell death, and cell cycle arrest by inducing DNA damage. Conclusions:The bacteria metabolite PAA increased CRC cell death by endoplasmic reticulum stress-induced autophagy and downregulation of the PI3K/AKT/mTOR and ERK pathways. PAA also potentiated chemotherapeutic efficacy of 5-FU through induction of DNA damages. These findings warrant further exploration of PAA as a potential CRC biomarker and novel therapeutic agent. Citation Format: Sylvain Ferrandon, Cheng Kong, Joseph Fedro, Rami-James Aoun, Chureeporn Chitchumroonchokchai, Steven Clinton, Matthew F. Kalady. Phenylacetaldehyde induces apoptosis through endoplasmic reticulum and potentiates the effect of 5-FU treatment in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1830.

Diet composition and nutrient availability play critical roles in intestinal stem and progenitor cell function and proliferation. Here, we show that stearoyl-CoA desaturases (SCDs) are regulated by nutrient abundance and link intracellular lipid metabolism to intestinal homeostasis. Pharmacological inhibition or genetic deletion of Scd1 and Scd2 in intestinal mouse organoids disrupted lipid desaturation, induced endoplasmic reticulum (ER) stress, and impaired stem and progenitor cell proliferation, effects largely mitigated by oleic acid supplementation. Intestine-specific deletion of Scd1 and Scd2 reduced the number of LGR5+ stem cells in vivo and was accompanied by metabolic rewiring and expansion of transient amplifying cells. Loss of Scd1 and Scd2 also reduced epithelial regeneration capacity following irradiation and exacerbated tissue damage and inflammation in a DSS-induced colitis model. Together, these findings reveal important SCD dependencies and metabolic adaptations in intestinal stem and progenitor cells that are necessary for epithelial regeneration and repair following injury.

748 Background: Metastatic neuroendocrine bladder cancer is a rare and aggressive malignancy characterized by poor prognosis and limited effective treatment options. Standard chemotherapy has shown limited success, necessitating novel therapies. We hypothesized that adding immunotherapy to chemotherapy would improve overall survival (OS) in these patients. Methods: We conducted a retrospective cohort study of 1,410 patients diagnosed with metastatic neuroendocrine bladder cancer between 2004 and 2020 using the National Cancer Database (NCDB). Treatment groups included no treatment, chemotherapy alone, and combined immunochemotherapy. Survival outcomes were analyzed using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards regression models, adjusting for age, tumor size, Charlson-Deyo comorbidity score, and residential area. Results: Median OS was 1.8 months (95% CI: 1.6-2.0) for patients receiving no treatment (n=460), 9.6 months (95% CI: 8.9-10.1) for chemotherapy alone (n=860), and 11.7 months (95% CI: 9.6-14.8) for combined immunochemotherapy (n=90) (P < 0.001 for immunochemotherapy vs. both other groups). Further analysis revealed that first-line immunotherapy initiated within 30 days of chemotherapy (n=21) significantly improved OS (median 11.6 months; 95% CI: 6.8–16.1; P=0.0374) compared to chemotherapy alone. Notably, immunotherapy initiated after 30 days (n=69, median OS 12.4 months; 95% CI: 9.0–14.8; P=0.0264), whether as first-line or second-line therapy, also showed superior efficacy to chemotherapy alone. These findings suggest that if first-line immunotherapy is not administered, subsequent immunotherapy should still be considered. Multivariable Cox regression analysis showed that immunochemotherapy compared to chemotherapy alone was associated with a lower hazard for death (HR = 0.80; 95% CI: 0.66-0.97; P = 0.0242), while patients receiving no treatment had an increased risk of death (HR = 3.50; 95% CI: 3.00-3.90; P < 0.0001). Additional factors associated with increased mortality included older age, larger tumor size, and higher Charlson-Deyo score. Conclusions: Adding immunotherapy to chemotherapy significantly improved OS in metastatic neuroendocrine bladder cancer. First-line immunochemotherapy showed substantial benefits, but late initiation also improved outcomes. These findings support incorporating immunotherapy into first-line protocols and consider it for subsequent lines. Prospective clinical trials are needed to optimize immunotherapeutic strategies for this aggressive malignancy.

Immune checkpoint inhibitors (ICIs) have improved cancer survival rates, but only a small percentage of patients experience significant and sustained tumor responses. Recent evidence points to the gut microbiome as a modifiable factor that may improve the efficacy of ICIs. This study utilized a human clinical trial and an experimental model to assess whether a dietary intervention could enhance ICI therapeutic outcomes. Specifically, we investigated the effects of black raspberry nectar (BRB) consumption on the microbiome and subsequently in murine models of anti-PD1 cancer therapy. The BEWELL clinical trial was a randomized, placebo-controlled, cross-over dietary intervention trial where 40 individuals received 80 mL of BRB for 4 weeks or placebo for 4 weeks. The BRB altered the participants’ microbiomes, significantly enriching microbes in the family Lachnospiraceae. Mice were gavaged with microbiomes from human participants who exhibited significant Lachnospiraceae enrichment post-BRB dietary intervention showed substantial reductions in tumor volume following anti-PD1 therapy. These results suggest that Lachnospiraceae may be key in enhancing ICI response. To further isolate the impact of specific microbes, we focused on Blautia, a representative Lachnospiraceae genus, to determine whether its presence could individually improve ICI therapeutic outcomes. Mice gavaged with Blautia-enriched microbiomes and provided anti-PD1 therapy demonstrated significantly lower tumor growth rates (p-value = 0.012) and a higher frequency of tumor-free status than controls (78% vs60%). A metabolomic analysis revealed distinct metabolic changes, with L-carnitine levels elevated in mice showing smaller tumors (p-value = 0.013). No significant changes were observed in butyrate, indole-derivatives, or inosine, which were previously shown to alter ICI response, suggesting a novel mechanism. Our findings underscore the potential of Lachnospiraceae, particularly Blautia, in improving cancer treatment outcomes. By extending human dietary modifications into preclinical models, this study reveals a promising strategy for using microbiome composition as a tool to enhance ICIefficacy. Shiva Jahanbakhshi, Amna Bibi, Rebecca Hoyd, Caroline Dravillas, Nyelia Williams, Shiqi Zhang, Aaditya Pallerla, Shankar Suman, Joseph Amann, Mounika Goruganthu, Tamio Okimoto, Yangyang Liu, Marisa A. Bittoni, Ni Shi, 2 Bailey Conrad, Lane Nevers, Kristen Heitman, Maxine Webb, Elizabeth M. Grainger, Madison Grogan, Christian Quiles, Tong Chen, Carolyn Presley, Lang Li, Patrick Bradley, Yael Vodovotz, David P. Carbone, Steve K. Clinton, Jiangjiang Zhu, Daniel Spakowicz. Gut microbiome modulation by a black raspberry nectar for improving anti-PD1 therapy effectiveness in pre-clinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2377.

597 Background: Early detection of recurrence in urothelial carcinoma (UC) and renal cell carcinoma (RCC) may improve patient outcomes. Conventional imaging techniques may not identify early molecular relapses that precede clinical relapse. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for the early detection of disease relapse. This study aims to evaluate the concordance of molecular relapses by ctDNA and radiographic progression in patients with UC and RCC who are off immunotherapy due to intolerance of side effects or completion of treatment. Methods: We conducted a retrospective study of locally advanced/advanced UC and RCC patients who were treated at The Ohio State University James Cancer Hospital from November 2021 to September 2024. Patients who completed planned immunotherapy followed by imaging and ctDNA surveillance were included. ctDNA levels were measured using the Signatera tissue informed assay at intervals of 4 to 12 weeks. Imaging surveillance schedules were at the treating physician discretion. Patient demographics, clinical characteristics, and ctDNA levels were recorded and analyzed. Results: A total of 36 patients were included: muscle-invasive bladder cancer (MIBC, n = 10), metastatic urothelial carcinoma (mUC, n = 10), locally advanced RCC (n = 4), and metastatic RCC (mRCC, n = 12). The median follow-up was 39.5 weeks (range: 1–138 weeks), with a median age of 67.5 years (range: 41–83 years), and 72.2% were male. At the time of immunotherapy discontinuation, ctDNA was negative in all patients except one mRCC patient (ctDNA 0.95 MTM/mL). During surveillance, 9 patients (25%) - 5 mUC and 4 mRCC - became ctDNA-positive, of which, eight showed radiographic progression, while one mRCC patient (ctDNA 0.15 MTM/mL) did not. None of the 27 patients (75%) that continued to have negative ctDNA had radiographic progression. For the 8 patients with progression, the median time from stopping immunotherapy to ctDNA relapse was 17.5 weeks (range: 11–42 weeks). The median time from ctDNA relapse to imaging-confirmed progression was 22 weeks (range: 13–43 weeks). At progression, ctDNA levels ranged from 0.08 to 136.49 MTM/mL (median: 2.33 MTM/mL). Six of the 20 metastatic patients (30%) relapsed despite negative ctDNA at immunotherapy discontinuation. Conclusions: ctDNA positivity occurs much earlier and is highly concordant with radiographic progression in patients with locally advanced/advanced UC and RCC under post-immunotherapy surveillance. These findings suggest that ctDNA is a promising tool for early disease relapse detection in these patients. Further studies are warranted to validate these results and establish standardized ctDNA surveillance protocols.

BACKGROUND:Increasing evidence suggests the unique susceptibility of estrogen receptor and progesterone receptor negative [ERPR(-)] breast cancer to dietary fat amount and type. Dietary n-3 (ω-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may modulate breast adipose fatty acids and downstream metabolites to counteract procarcinogenic signaling in the mammary microenvironment. OBJECTIVES:We aimed to determine effects of ∼1 to 5 g/d EPA+DHA over 12 mo on breast adipose fatty acid and oxylipin profiles in survivors of ERPR(-) breast cancer, a high-risk molecular subtype. METHODS:We conducted a proof-of-concept 12-mo randomized double-blind trial comparing ∼5 g/d and ∼1 g/d EPA+DHA supplementation in females within 5 y of completing standard therapy for ERPR(-) breast cancer Stages 0 to III. Blood and breast adipose tissue specimens were collected every 3 mo for fatty acid, oxylipin, and DNA methylation (DNAm) analyses. RESULTS:A total of 51 participants completed the 12-mo intervention. Study treatments were generally well tolerated. Although both doses increased n-3 PUFAs from baseline in breast adipose, erythrocytes, and plasma, the 5 g/d supplement was more potent with differences (% total fatty acids) of 0.76 (95% confidence interval [CI]: 0.56, 0.96), 6.25 (95% CI: 5.02, 7.48), and 5.89 (95% CI: 4.53, 7.25), respectively. The 5 g/d dose also reduced plasma triglycerides from baseline, with changes (mg/dL) of 27.38 (95% CI: 10.99, 43.78) and 24.58 (95% CI: 9.05, 40.10) at 6 and 12 months, respectively. Breast adipose oxylipins showed dose-dependent increases in DHA and EPA metabolites. Distinct DNAm patterns in adipose tissue after 12 mo suggest potential downregulation of aberrant lipid metabolism pathways at the 5 g/d dose. CONCLUSIONS:Over 1 y, EPA+DHA dose-dependently increased breast adipose concentrations of these fatty acids and their derivative oxylipin metabolites and produced differential DNAm profiles involved in metabolism-related pathways critical to ERPR(-) breast cancer development. This distinct metabolic and epigenetic modulation of the breast microenvironment is achievable with high-dose n-3 PUFA supplementation. This trial was registered at clinicaltrials.gov as NCT02295059.

Background: Dietary intake of flavonoids, a class of plant (poly)phenols, is hypothesized to mediate a variety of beneficial health outcomes linked to fruits and vegetables (FV) intake. Absorbed flavonoids are metabolized and excreted in urine and may serve as biomarkers of FV intake and host metabolism, but defining the relationship of urinary biomarkers to the specific time of intake is unclear. Objectives: To characterize a targeted panel of 6 urinary flavonoids and determine the relationship to estimated dietary flavonoid intake over time in adults. Methods: Dietary flavonoid intake was estimated from both a 30-d food frequency questionnaire and 3-d diet records using the Phenol-Explorer database in 17 adults. Twenty-four-hour urine was collected, and a targeted panel of 6 urinary flavonoids (quercetin, phloretin, naringenin, hesperetin, kaempferol, and isorhamnetin) was quantified using high-pressure liquid chromatography-diode array detection (DAD). Results: Compared to estimated intakes from a 1 d or 3 d diet record, total urinary flavonoids were most strongly associated with total FV (excluding potatoes) (rs = 0.53, P = 0.028) and total FV flavonoid (rs = 0.60, P = 0.011) intakes estimated by a 2 d diet record (including the day before and the day of the 24-h urine collection). There were no significant correlations between urinary concentrations of flavonoids and estimated FV intake using a 30-d food frequency questionnaire (rs = 0.36, P = 0.16). Conclusions: Targeted flavonoid concentrations in a 24-h urine collection may serve as a biomarker for estimating dietary exposures over 2 d prior to completion of the urine collection, but not more distant dietary exposures.This trial was registered at clinicaltrials.gov as NCT03489213.

e16523 Background: msRCC is an aggressive cancer subtype. However, the impact of racial disparities in this population remains underexplored. This study aims to examine racial disparities in 3-year cancer-specific survival (CSS) and overall survival (OS) among patients diagnosed with msRCC. Methods: We retrospectively analyzed the data from the SEER database, including 2,122 patients diagnosed with msRCC between 2010 and 2020. Patients were categorized into racial groups: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Hispanic, Asian or Pacific Islander (API), and American Indian/Alaska Native (AIAN). 3-year CSS and OS were calculated, and racial differences in survival were assessed using multivariable Cox proportional hazards models, adjusting for demographic, clinical, and treatment variables. Results: NHB patients exhibited the worst 3-year CSS of 9.3% and OS of 8.6%, compared to 23.3% and 20.9% for NHW, 22.1% and 19.0% for Hispanic, 21.2% and 19.4% for API, and 23.4% and 20.7% for AIAN groups, respectively. Multivariable survival analyses revealed that NHB had a50% increased risk (HR=1.5, 95% CI=1.2-1.8, P<0.0001) of CSS and a 40% higher risk (HR=1.4, 95% CI=1.2-1.7) of OS compared NHW. Additionally, Hispanics had a 20% higher risk (HR=1.2, 95% CI=1.0-1.3, P=0.0331) of OS compared NHW. Markedly, the 3-year CSS and OS rates improved across all racial groups from the period of 2010-2015 to 2016-2020. Despite improvement, NHB patients continued to have the lowest rates of 3-year CSS and OS rates during the later period. ln multivariable survival analyses for 2016-2018, NHB patients faced an 80% increased risk (HR=1.8, 95% CI=1.3-2.4, P<0.0001) of CSS and a 60% higher risk (HR=1.6, 95% CI=1.2-2.2) of OS compared to NHW patients. Conclusions: Racial disparities in 3-year CSS and OS persist in msRCC, with NHB patients consistently exhibiting the poorest outcomes, even as survival rates have improved across all racial groups from 2016 to 2020. This improvement was likely contributed by recent advancements in immunotherapy. The underlying reasons for these disparities remain unclear but may involve genetic predisposition, tumor aggressiveness, or socioeconomic factors. Large-scale genetic and molecular studies are needed to uncover biological contributors and guide targeted interventions. Addressing these disparities is critical to advancing equity in msRCC patients.

Introduction: The treatment efficacy of prostate cancer (PCa) radiotherapy (RT) can be inadvertently affected by the concurrent usage of non-oncologic medications. Many studies have associated the intake of several non-oncologic drugs with cancer specific outcomes. In this study, we report the impact of daily non-oncologic medications including aspirin, metformin, and statins on time to progression for patients with high-risk PCa. Methods: Patients with high- and very high risk PCa (NCCN definition of Gleason score ≥ 8, prostate-specific antigen (PSA) ≥ 20, or ≥cT3a) who received definitive RT at two institutions were included in this analysis. Progression was defined as either biochemical (PSA > nadir + 2 ng/mL), locoregional (prostate or lymph nodes, biopsy-proven), or development of distant metastases. Progression-free survival (PFS) was defined as the time elapsed from the start of RT to progression or last follow-up. Cox proportional hazards models evaluated the associations between non-oncologic medications and PFS. Results: There were 237 patients eligible for this analysis, of which 47 (19.8%) and 178 (75.1%) had at least clinical T3 disease or at least Gleason 8 disease, respectively. During RT, 82 (34.6%), 88 (37.1%), and 29 (12.2%) patients were taking aspirin, statin, or metformin, respectively. Overall, 54 patients (22.8%) experienced disease progression. Neither aspirin nor statin usage had a significant association with PFS. Patients prescribed metformin displayed worse PFS compared to patients not taking metformin (aHR: 2.46, 95% CI: 1.06–5.72). Conclusions: Aspirin and statin usage was not associated with likelihood of progression in this large cohort of patients with high-/very high risk PCa. Metformin use was associated with poorer PFS, albeit with a small event rate due to fewer patients taking metformin. Further studies are needed to clarify the impact of common non-oncologic medication use on outcomes for patients with high-risk PCa.

Cancer outcomes have improved with immune checkpoint inhibitor (ICI) treatment; however, less than half of tumors respond. Emerging data show that some responses to ICI depend on the host's microbiome. Here, we explore a dietary intervention to modify the microbiome and determine the response to ICIs. Following preclinical studies showing the benefit of black raspberries, we conducted a human intervention trial called the BEWELL Study ([NCT04267874][1]). The intervention increased the abundance of pro-ICI-response microbes (PIRMs). In mouse models, participants' post-dietary intervention stool led to smaller tumor volumes following treatment with ICIs than pre-dietary intervention samples. One PIRM, Blautia obeum , was sufficient to improve ICI response. These results suggest that black raspberry nectar can modify the human gut microbiome to promote an improved response to ICIs. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04267874 ### Funding Statement Pelotonia, clinical trial award (DS) OSUCCC Division of Medical Oncology, seed grant (DS) Association for the Study of Lung Cancer, Lung Cancer Foundation of America and the Bristol Meyers Squibb Foundation, Young Investigator in Immuno-Oncology Award (DS) National Institutes of Aging grant 1K01AG070310 (DS) The Ohio State University Wexner Medical Center and The Ohio State University College of Medicine Clinical Research Center/Center for Clinical Research Management American Lung Association Innovator Award (DS) American Cancer Society Research Scholar (DS) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of The Ohio State University Comprehensive Cancer Center gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at https://github.com/spakowiczlab/dmm21 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04267874&atom=%2Fmedrxiv%2Fearly%2F2025%2F01%2F17%2F2025.01.16.25320666.atom

BACKGROUND:Bladder cancer is unique among visceral malignancies in that urine, which can be easily obtained, has prolonged contact with bladder tumors. Urinary biomarkers offer the potential to provide insight into the host and tumor immune microenvironment to guide therapeutic strategies. We evaluated the immune cellular composition of urine (urine-derived lymphocytes (UDLs)) versus tumor (tumor-infiltrating lymphocytes (TILs)). METHODS:We employed high-dimensional flow cytometry analyses on immune cells from tumors (TILs), urine (UDLs), and peripheral blood (peripheral blood mononuclear cells) among patients with bladder cancer. We performed multiplexed immunofluorescence (mIF) of matched tumors to provide spatial context to our findings, comparing deep/invasive and superficial/urine-facing regions of matched tumors. RESULTS:Our findings suggest that the CD4+ and CD8+ T cell subsets of UDLs characterized by flow cytometry had similar phenotypic profiles to those found in TILs (cell clusters quantified by multidimensional scaling and differentiation states). Results of mIF imaging with a panel of phenotypic and functional T cell markers suggested that UDLs reflected TILs in both superficial and deep tumor sections. We also found sex-dependent patterns in TILs and UDLs, indicating the male bladder cancer tumor microenvironment is enriched in exhausted CD4+ and CD8+ T cells, while the female bladder cancer microenvironment is enriched for activated T cells. CONCLUSIONS:Assessment of UDLs opens avenues of non-invasive biomarker development in clinical settings where bladder cancer TILs are hypothesized to predict clinical response. UDLs may also reflect sex-based differences in antitumor immunity.

Cancer survivors face an increased risk of cardiovascular disease (CVD) due to treatment-related toxicity, lifestyle factors, and comorbidities. Addressing CV health is crucial for improving quality of life and long-term outcomes. The American Heart Association's Life's Essential 8 framework highlights modifiable determinants of CV health, emphasizing early detection and monitoring. Mobile health (mHealth) technologies, such as wearables and smartphone apps, offer continuous tracking, yet their applications in cancer survivorship remain unclear. This review systematically characterizes the types of mHealth technologies used to monitor CV health in cancer survivors, focusing on the specific data collected (major adverse CV events, CV risk factors, and surrogate endpoints) and the use of active versus passive collection methods. A systematic search of PubMed, Scopus, Embase, and Web of Science identified studies published between January 1, 2016, and June 13, 2024. Eligible studies included observational and interventional designs assessing at least one CV outcome using mHealth. Data were extracted on design, technology type, and outcomes. Risk of bias was evaluated using the Cochrane RoB-2 and ROBINS-I tools. Fourteen studies (13 interventional, one observational) met criteria. Physical activity was the most monitored risk factor, followed by HR. The most common technologies were mobile apps and commercial wearables. Passive methods typically captured PA and HR, while active methods captured PA, symptom tracking, and diet. A key finding was the lack of integration with electronic medical records, highlighting a gap in clinical implementation. mHealth provides scalable tools to track CV health indicators in cancer survivors. Findings highlight the potential to support practice by enabling remote oversight of risk-reducing behaviors and guiding lifestyle interventions. However, we also identified gaps, including the underutilization of biomarkers (e.g., HRV) and the lack of integration with electronic records. Future research must address these gaps to translate real-time data into clinical insights and optimize survivorship care.

84 Background: Lutetium-177-vipivotide tetraxetan ( 177 Lu) was approved in 2022 for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with prior androgen receptor signaling inhibition (ARSI) and a taxane. The impact of 177 Lu in a non-trial setting is limited. Methods: We retrospectively reviewed records of mCRPC pts who received ≥1 dose of 177 Lu at The Ohio State University from 3/2022-3/2024. Demographics, tumor histology, metastasis sites (mets), treatment (Tx) history, standardized uptake value max (SUVm), and prostate-specific antigen (PSA), at baseline (BL) and post-Tx were collected. SUVm was defined as the highest SUV from a single lesion. Outcomes were PSA response, PSA50, radiographic progression-free (rPFS) by PCWG3, and overall survival (OS). Descriptive statistics, Mann-Whitney, Chi-square, and Cox regression model were used to assess impact. Results: A total of 152 pts were included with a median follow-up of 9 months (0.1-23 m). The median age was 70 years (46-92 y), with 39% having de novo metastatic disease, and 61% had Gleason grade group ≥4. The common mets were bone (91%), lymph node (68%), and visceral (34% with 17% liver and 8% lung). The majority received prior taxanes and ARSI, and 20% radium-223. The median lines of prior Tx was 5.The median BL PSA was 56.3 ng/mL, and the median BL SUVm was 30.4. Post-Tx, 64% showed a PSA response, and 46% achieved PSA50. Among the pts with available imaging, 17% had partial response, 12% stable disease, and 48% disease progression.Tx was discontinued in 62% for:radiographic progression (66%), PSA-only progression (7%), clinical decline (24%), and toxicity (3%). At the data cutoff, mortality was 50%. Median PFS and OS was 6.7 m, and 12.2 m respectively. BL SUVm was associated with improved PSA50 (p=0.01), rPFS (p<0.01), and OS (p=0.01), and liver mets associated with worse OS (p<0.01). Conclusions: In this retrospective study of 177 Lu, we see similar PSA and PSA50 responses to reported trials. However, PFS was shorter, and mortality was higher, likely related to the use of 177 Lu in heavily treated pts with few remaining options. Optimizing biomarkers to predict Tx benefit and resistance are needed.

870 Background: Studies cite that 10-24% of patients (pts) with urothelial carcinoma (UC) have a pathogenic germline variant (var), but few have looked at association with outcomes. We aimed to identify the frequency of germline pathogenic vars (PV) in UC and hypothesized they would be associated with cancer-related outcomes. Here we present germline results from the largest reported, fully clinically annotated cohort of pts with UC. Methods: We performed a single center retrospective review of all pts with a diagnosis (dx) of bladder, renal pelvis, ureter, or urethra cancer who underwent clinical germline targeted panel genetic testing from 2018 to 2024. We also included all pts with the same dx enrolled on an institutional protocol that performed germline whole exome sequencing (WES) for research. We analyzed the 77 genes from WES most frequently included in the targeted panels. We classified all vars as pathogenic, variant of unknown significance (VUS), or benign. Results: We included 267 pts. Median number of genes tested was 77 (range 1-93) with 83.9% of pts completing a panel of ≥77 genes. Of 267 pts, 48 (18%) had a PV, 138 (52%) had a VUS without a PV, and 81 (30%) had no germline var. The most common PVs were in CHEK2 (n = 5/48 [11%]), ATM (9%), MUTYH (9%), MSH2 (9%), TP53 (7%) and MLH1 (7%). Among the 48 pts with a PV, 12 (25%) had Lynch syndrome and 25 (52%) had a non-Lynch DNA Damage Repair gene var. Of 256 pts with urothelial histology, 47 (18%) had a PV. Of 7 pts with pure squamous histology, 1 (14%) had a PV in ATM , 4 (57%) had a VUS. Three pts with rare histologies of small cell, rhabdomyosarcoma, and adenocarcinoma had a VUS in ATM, RET, or POLD1, respectively. Of 48 pts with a PV, only 12 (25%) ever developed metastatic disease. Comparing pts with PVs (n=48) to not (n=219), we found no significant difference in median age at dx, age at dx ≥ 60, sex, race, ethnicity, smoking history, median number of 1 st degree family members with a dx of cancer, or clinical stage at dx. Pts with a PV had no significant difference in primary tumor location, however pts with Lynch syndrome were more likely to have an upper tract tumor (p = 0.002). Adjusting for clinical stage, there was no significant difference in overall survival between pts with a PV compared to without. Three of 12 pts with Lynch received an immune checkpoint inhibitor (ICI) for non-muscle invasive, muscle invasive, or metastatic disease, respectively, and all had prolonged responses without recurrence at 44, 12, and 70 months of follow-up. Conclusions: Germline PVs were detected in 18% of pts with UC. We confirmed the association of Lynch syndrome with upper tract disease and favorable response to ICI. Germline genetics of rare histologic variants warrants further investigation. Our findings support genetic testing in all pts with UC, including early-stage disease. Further study of ICIs for early-stage UC in Lynch syndrome is needed. Analysis of a larger cohort and response to specific treatments is ongoing.

Plant-based milk alternatives (PBMAs) are increasingly consumed as a dairy alternative []. Plant foods are rich sources of (poly)phenols, but concentrations of these bioactive phytochemicals in processed PBMAs are not well documented. We procured twenty-seven PBMA products of 6 types (almond, coconut, oat, pea, rice, and soy) for (poly)phenol analysis. Samples were analyzed via ultra high-performance liquid chromatography-diode array with mass spectrometry. The (poly)phenol content of PBMAs varies and is dependent on plant source, brand, and added flavorings. Soy milk had the highest concentration and rice milk had the lowest (91.9 +/- 2.7 and 0.9 +/- 0.2 mean mg +/- SD/cup serving, respectively). Almond milk, the most widely consumed PBMA, averaged 12.1 +/- 8.2 mg/cup serving, but the majority of (poly)phenols are derived from added flavorings. PBMAs contain a wide range of potentially bioactive (poly)phenols and may contribute significantly to overall dietary (poly)phenol intake with the potential to impact health outcomes.

Preclinical and clinical data suggest that androgen receptor signaling strongly contributes to bladder cancer development. The roles of the androgen receptor in bladder carcinogenesis have obvious implications for understanding the strong male sex bias in this disease and for potential therapeutic strategies as well. In this review, we summarize what is known about androgen receptor signaling in urothelial carcinoma as well as in tumor-infiltrating immune cells, reviewing preclinical and clinical data. We also highlight clinical trial efforts in this area.

Background: Evidence-based lifestyle programs including the Diabetes Prevention Program can delay an individual’s risk of developing type 2 diabetes. Identifying which individuals are less likely to enroll in these programs and tailoring recruitment approaches to encourage participation among those with perceived barriers is an effective strategy to increase engagement in health promotion. This study aimed to identify the pre-enrollment differences in biometric trends between individuals with prediabetes who did and did not express interest in free worksite diabetes prevention programs.Subjects and Method: This retrospective cohort study was conducted among individuals in the Midwest enrolled in a private insurance plan from 2011 to 2014. Data was combined from annual biometric screenings and a health survey. Demographic characteristics were summarized for the study population (n=2,066). The dependent variable for this study was interest in the DPP, while the independent variables included body mass index, waist circumference, body weight, lipid measurements, and blood pressure. Linear mixed models with random intercepts were used to compare bio-metric trajectories for body mass index, waist circumference, body weight, lipid measurements (triglycerides and cholesterol), and blood pressure for the two groups.Results: No differences were observed in biometric trends for those who did and did not choose to enroll in the free worksite program.Conclusion: Examining pre-enrollment biometric trend data is a relatively novel approach to evaluating engagement in health programs. More research is needed to understand how this information can be used to identify an individual’s interest in enrolling in health programming.